Mutations in the progranulin gene cause frontotemporal dementia (FTD), the second most common age-related dementia after Alzheimer's disease. FTD results in selective degeneration of the frontal and temporal cortices, changes in behavior and personality, and eventual cognitive decline. A mouse model of progranulin depletion is characterized by increased brain inflammation and deficits in social interaction. However, it is unknown how loss of progranulin contributes to these cellular and behavioral deficits in mice or humans. The goals of this proposal are to elucidate the importance of microglia-derived progranulin in promoting proper neuronal function and survival and to determine whether its neuroprotective effect against inflammation is mediated through inhibition of NFB. Aim 1 will test the hypothesis that microglial progranulin is essential for protection against inflammation and the associated neuronal injury. A range of experimental approaches, including in vitro co-culture of neurons and microglia from progranulin wildtype or knockout mice, characterization of a conditional progranulin knockout with deletion driven specifically in cells of myeloid origin, and lentiviral replacement therapy of progranulin in progranulin knockout mice, will be employed to address this hypothesis. Aim 2 will test the hypothesis that progranulin mediates its protective effects by inhibiting NFB. NFB activation and release of target genes, such as iNOS, TNF, IL-1, and IL-6, in primary cultures and conditional progranulin knockout mice will be measured in Aim 2A. Aim 2B will determine whether inhibiting NFB in progranulin knockout cells or mice rescues neuronal and behavioral deficits. Finally, Aim 2C will employ a genetic approach to conditionally delete IKK (which leads to activation of NFB) from cells of myeloid origin in conditional progranulin knock-out mice to determine whether inactivating the NFB pathway rescues the phenotype observed in progranulin-deficient mice. These studies will employ a range of cellular, biochemical, molecular, and behavioral assays to better understand the mechanisms underlying progranulin-mediated neuronal protection and potentially offer new therapeutic approaches for the treatment of FTD. Moreover, understanding progranulin-mediated neuroprotection may be useful for the treatment of other neurodegenerative diseases that involve inflammation, such as Alzheimer's disease and Parkinson's disease.